PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate
Abstract Emerging evidence indicates that metabolic signals—including nutrient availability, biosynthetic intermediates, and energy balance—are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62111-3 |
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| author | Pianpian Lin Yijun Qi Huiying Chu Hongyu Wu Yajuan Zhang Xiaolan Huang Chen Li Xiaoyan Xu Hong Gao Rong Zeng Guohui Li Weiwei Yang |
| author_facet | Pianpian Lin Yijun Qi Huiying Chu Hongyu Wu Yajuan Zhang Xiaolan Huang Chen Li Xiaoyan Xu Hong Gao Rong Zeng Guohui Li Weiwei Yang |
| author_sort | Pianpian Lin |
| collection | DOAJ |
| description | Abstract Emerging evidence indicates that metabolic signals—including nutrient availability, biosynthetic intermediates, and energy balance—are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA cycle, peaks during mitosis (M phase) and is detected by the glycolytic enzyme ATP-dependent 6-phosphofructokinase 1 muscle isoform (PFKM), accelerating mitotic progression. Mechanistically, citrate binds PFKM, disrupting its tetrameric structure into dimers. Dimeric PFKM interacts with nucleosomes and phosphorylates histone H3 at serine 10 (H3S10), functioning as a protein kinase to promote mitosis and cell proliferation. Structural simulations reveal that PFKM binds nucleosomes optimally when H3S10 aligns with its catalytic site. Disrupting citrate-PFKM or PFKM-H3 interactions reduces H3S10 phosphorylation, delays mitosis, and suppresses tumor growth and T-cell proliferation. Our findings demonstrate that PFKM acts as a citrate sensor, coupling metabolic signals to cell cycle regulation. |
| format | Article |
| id | doaj-art-5e61705bed2e4647a96499dcfc33168d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5e61705bed2e4647a96499dcfc33168d2025-08-20T03:43:00ZengNature PortfolioNature Communications2041-17232025-07-0116112010.1038/s41467-025-62111-3PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citratePianpian Lin0Yijun Qi1Huiying Chu2Hongyu Wu3Yajuan Zhang4Xiaolan Huang5Chen Li6Xiaoyan Xu7Hong Gao8Rong Zeng9Guohui Li10Weiwei Yang11Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell BiologyKey Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesInterdisciplinary Research Center for Biology and Chemistry, Liaoning Normal UniversityKey Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell BiologyKey Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell BiologyKey Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of SciencesCenter for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of MedicineMass Spectrometry & Metabolomics Core Facility, Biomedical Research Core Facilities, Westlake UniversityKey Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell BiologyKey Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell BiologyInterdisciplinary Research Center for Biology and Chemistry, Liaoning Normal UniversityKey Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell BiologyAbstract Emerging evidence indicates that metabolic signals—including nutrient availability, biosynthetic intermediates, and energy balance—are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA cycle, peaks during mitosis (M phase) and is detected by the glycolytic enzyme ATP-dependent 6-phosphofructokinase 1 muscle isoform (PFKM), accelerating mitotic progression. Mechanistically, citrate binds PFKM, disrupting its tetrameric structure into dimers. Dimeric PFKM interacts with nucleosomes and phosphorylates histone H3 at serine 10 (H3S10), functioning as a protein kinase to promote mitosis and cell proliferation. Structural simulations reveal that PFKM binds nucleosomes optimally when H3S10 aligns with its catalytic site. Disrupting citrate-PFKM or PFKM-H3 interactions reduces H3S10 phosphorylation, delays mitosis, and suppresses tumor growth and T-cell proliferation. Our findings demonstrate that PFKM acts as a citrate sensor, coupling metabolic signals to cell cycle regulation.https://doi.org/10.1038/s41467-025-62111-3 |
| spellingShingle | Pianpian Lin Yijun Qi Huiying Chu Hongyu Wu Yajuan Zhang Xiaolan Huang Chen Li Xiaoyan Xu Hong Gao Rong Zeng Guohui Li Weiwei Yang PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate Nature Communications |
| title | PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate |
| title_full | PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate |
| title_fullStr | PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate |
| title_full_unstemmed | PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate |
| title_short | PFKM phosphorylates histone H3 and promotes mitotic progression by sensing the levels of citrate |
| title_sort | pfkm phosphorylates histone h3 and promotes mitotic progression by sensing the levels of citrate |
| url | https://doi.org/10.1038/s41467-025-62111-3 |
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